Endothelial BMP6 Drives Hemodynamic-Dependent VSMCs Calcification in Carotid Atherosclerosis

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Atherosclerosis
• Vascular Calcification

Background:

• Carotid atherosclerosis (CAS) is a significant cause of ischemic stroke, with vascular calcification exacerbating disease progression.
• The precise molecular pathways governing vascular calcification in CAS are not fully understood.
• Bone morphogenetic proteins (BMPs) are implicated in calcification, but BMP6 signaling's role remains unclear.

Purpose of the Study:

• To investigate the role of BMP6 in vascular calcification within carotid atherosclerosis.
• To elucidate the underlying molecular mechanisms connecting BMP6 to calcification in CAS.

Main Methods:

• Single-cell RNA sequencing of human CAS plaques to identify cell-cell interactions and gene expression patterns.
• In vitro studies using endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) to assess BMP6 function.
• In vivo experiments using endothelium-specific BMP6 knockout (BMP6^ECKOApoE^-/-) and overexpression mouse models.
• Analysis of the impact of disturbed blood flow on BMP6 expression and calcification.

Main Results:

• Single-cell RNA sequencing revealed ECs with high BMP6 expression interacting with VSMCs via BMP signaling.
• BMP6 directly induced osteogenic differentiation of VSMCs in vitro.
• BMP6 activated the SMAD signaling pathway.
• Endothelium-specific BMP6 knockout reduced calcific lesions, while overexpression exacerbated them.
• Disturbed flow conditions increased BMP6 expression by suppressing Krüppel-like factor 4, linking hemodynamic forces to calcification.

Conclusions:

• BMP6 is a critical regulator of vascular calcification in carotid atherosclerosis.
• EC-VSMC communication mediated by BMP6, influenced by hemodynamic stress, drives calcification.
• Targeting BMP6 signaling presents a potential therapeutic strategy for CAS.